- In the current paradigm, autoimmune disease evolves when "forbidden clones" recognize a disease-inducing antigen and initiate an immune response. This application presents a novel hypothesis on the involvement of T lymphocytes in human autoimmune disease and plans to investigate this novel disease model in patients with RA. The principal investigator proposes that autoimmunity results from abnormalities in the formation of the T cell repertoire and that more than 70% of the T cells present in a patient are pathologically relevant. The rationale for this hypothesis comes from preliminary data demonstrating that the repertoire of CD4 T cells in patients with RA is extensively altered and is characterized by widespread oligoclonality and loss in diversity. By measuring the frequency of arbitrarily chosen TCR beta-chains in circulating CD4 T cells, the principal investigator determined that, on average, individual TCR beta-chains are present at tenfold higher frequencies in RA patients than in age-matched controls, indicating clonal proliferation. Telomere length analysis of CD4+ T cells demonstrated that the vast majority of T cells in RA patients had an extensive replicative history. Analysis of proliferating CD4 T cells indicated an increased T cell turnover. These aberrations were not present in patients chronically infected with hepatitis C virus, suggesting that chronic antigenic stimulation cannot induce global abnormalities in the repertoire. In the current project, this hypothesis is to be tested with the ultimate goal of understanding mechanistic principles inducing repertoire derangements. In the first specific aim, the principal investigator will explore whether increase CD4 turnover and loss of T cell diversity are found in multiple autoimmune diseases or are specific for RA, and whether aberrations in the CD4 repertoire are genetically controlled and can be detected in siblings and offspring of patients. The second specific aim focuses on mechanisms inducing widespread T cell proliferation, oligoclonality, and loss of diversity. Such aberrations could be related to defects in T cell influx, an imbalance of clonal expansion and clonal downsizing, or widespread autorecognition. Accordingly, the repertoire of naive CD4 T cells will be analyzed, the dynamics of antigen-specific T cell clones in vivo after antigenic vaccination (influenza) will be studied, and the precursor frequency of CD4 T cells reactive to diverse autoantigens will be evaluated. The principal investigator anticipates that confirmation of the unexpected preliminary findings will fundamentally change the way for understanding RA and other autoimmune diseases, and open new direction for therapy.